Process of preparing alkyl-uric acid.



UNITED STATES PATENT OFFICE.

FRITZ ACI'I, OF MANNHEIM, GERMANY, ASSIGNOR TO 0. F. BOEHRINGER 8tSOEHNE, OF VVALDHOF, GERMANY.

PROCESS OF PREPARING ALKYL-URIC ACID.

SPECIFICATION forming part of Letters Patent No. 631,761,dated August22, 1899. Applioatien filed April 16, 1898. Serial No. 677,855. (Nospecimens.)

To all whom it may concern:

Be it known that I, FRITZ AOH, a citizen of the German Empire, residingat Mannheim, in the Empire of Germany, have in vented certain new anduseful Improvements in Preparing Alkylized Uric Acids; and I do herebydeclare the following to be afull, clear, and exact description of theinvention, such as will enable others skilled in the art to which itappertains to make and use the same.

This invention relates to the preparation of alkyl derivatives of uricacid proper, or, in other words, of alkyl-uric acids, with particularreference to obtaining such alkyl derivatives by direct methods.

Hitherto only the following members of the isomeric series of monomethyland dimethyluric acids have been obtainable by direct methylation ofuric acid: first, alpha-mono methyl-uric acid, which, according torecent investigations,has the structural formula corresponding to3-methyl-uric acid and which has been prepared by Hill and Mabery,(American Chemical Journal, Vol. 2, page 305, and Bem'chte der DeutschenOhemischen Gesellschafl,Vol. 9, page 370,) and by Emil Fischer, (GermanPatent No. 91,811, and additional patents Nos. 92,310, 93,112, and94:,631, and in Letters Patent of the United States Nos. 616,656,616,700, 621,804, and 621,805,) second, 9-methyl-nric acid, preparedbyEmil Fischer, (Beriehte der Deutschen Chemischen Gesellschaft,Vol. 17,page] 777;) third, 3-9-dimethyluric acid, prepared by Hill and Maberyand by Emil Fischer, (German Patent No. 91,811 and additional patents,)and, fourth, 7-9-dimethyl-uric acid, prepared by Emil Fischer,(Berichte, Vol. 17, page 1780.)

In the course of my researches and investigations in this field I havesucceeded in devising a method whereby I am enabled to prepare 7-methyl-uric acid and 3-7-dimethyluric acid, which hitherto could beobtained only by indirect methods, directly from uric acid. This newmethod involved in my invention, broadly considered, consists in thereduction of oxymethylene derivatives of uric acids, which compounds,together with their modes of preparation, are set forth in anapplication by myself and Lorenz Ach, filed April 21, 1898, Serial No.678,331.

While it is true that the usual alkylizing agents under the most variedconditions never act first upon the nitrogen atom occupying the position(7) in the uric-acid molecule, (see the nomenclature adopted by EmilFischer in Bem'chte, Vol. 30, page 557,) still under the process setforth in the aforesaid application the formic aldehyde is bound to theuric acid in the position (7) forming 7-oxymethylene-uricacid.Thislattercoinpound,I have found, may readily and directly be convertedinto 7-methyl-uric acid by reduction.

In an analogous manner and as set set forth in the aforesaid application7-oXymethylene-3- methyl-uric acid,which may be converted into 3-7-dimethyl-uric acid, may be obtained from the action of formic-aldehydeon 3-methyl-uric ,acid. Finally,7-oxymethylene-1-3-dimethyluric acid,obtained in the manner disclosed in the aforesaid application maybereduced, according to my present invention, to 1-3-7- trimethyl-uricacid or hydroXy-caffein. This reaction, moreover, seems to besusceptible of a still more general application. The process ofreduction of the oxymethylene uric acids is best carried out in acidsolutionssuch as, for-example, hydrochloric acidin con nection with tin.Such reduction takes place according to the following scheme:

where R denotes a molecule of uric acid proper or an alkyl-uric acidless the nitrogen atom in the position (7).

In the following detailed description I have illustrated my invention bythree examples, which embody what I consider the preferable ,manner ofcarrying the same into effect.

of caustic potash of eighty-per-cent. strength- While gently warming.The solution is then allowed to cool to room temperature, and there arethen added thereto 1.6 parts of concentrated solution of formicaldehyde. The whole is then allowed to stand at room temperature. Afterthe lapse of several hours (from about twenty to twenty-five hours) thestill clear solution is acidulated with H01 and treated with charcoal byshaking. After filtering the liquor the colorless filtrate is al.- lowedto stand, when the oxymethylene-uric acid will be thrown out in the formof coarse shining prismatic crystals, which are then cleanedby washingwith alcohol and ether and drying on the water-bath. The analysis ofthese crystals gives figures corresponding to the formula O H N O +I-I Oor Hi -CO oo Q-N. 011,011

c0+11,0. HNC-NH The Water of crystallization is slowly driven 0d byheating for a longer period at a temperature of from 120 to 130cent-igrade. The oxymethylene-uric acid,like uric acid proper, gives astrong murexide test with nitric acid or chlorin water and reducesammoniacal silver solution in the cold.

The new product has no meltin g-point, but turns brown when heatedbeyond 320 centigrade and is decomposed at a still higher temperature,the decomposition being attended with darkening and frothing. It isreadily recrystallized from water by boiling a shorttime after adding itthereto. It is thus obtained in the form of fine acicular crystals orshort colorless prisms. On protracted boiling with water formaldehyde issplit off and the uric acid proper regenerated.

Oxymethylene-uric acid is readily soluble in dilute alkalies.Concentrated alkali-lyes precipitate the corresponding salts after ashort time in the form of colorless needles united to form globularaggregates.

The potassium salt of oxymethylene-uric lized acid urate of potassium itthe latter is added to five times its weight of concentrated I solutionof formic aldehyde and the Whole allowed to remain together for aconsiderable period of timesay about thirty to forty hoursthe wholebeing preferably shaken or agitated. The excess of formaldehyde solutionis then removed by siphoning, decanting, or otherwise and then washingwith alcohol. From the potassium salt so obtained the above-describedoxymethylene-uric acid is obtained by supersaturating with mineralacids.

For the preparation of the F-methyl-uric acid I take one part of theoxymethyleneuric acid in a finely-powdered condition and dissolve thesame in twenty-five parts, by Volume, of fuming hydrochloric acid, andafter heating such solution to 45 centigrade I add thereto from six toseven parts of tin. This temperature of the reduction mixture ismaintained until the tin has been completely dissolved. Preferably themass is stirred or agitated diligently. The resultant colorless solutionis't-hen put on the water-bath and evaporated to dryness, as nearly aspossible. The residue is then taken up with fine spirits (alcohol) Whilegently heating, (about centi-. grade.) Under these conditions the 7-methyluric acid which has been formed remains in the form of acolorless crystalline mass. If the reactions have been properlyconducted, the same is obtained in a perfectly pure condition after oncerecrystallizing from water. It possesses all of the characteristicproperties which have been enumeratedfor this acid in Bem'chte derDeutschen Ohemischen Gesellschaft, Vol. 28, page 2492.

II. Preparation of 3 7 dimeihyl uric aoid.As the starting material inthe manufacture of this uricacid I employ 3-1nethyl- 7-oXymethylene-uric acid, whose mode of preparation and characteristicsare described and covered in the aforesaid application Serial No.678,331. I will first describe these for the purpose of a fulldisclosure of my invention.

Preparation of 3 methyl mag methylenem'ic acid.-I take one part of3-monomethyluric. acid and add thereto 1.8 parts of potashlye(potassium-hydrate) of twenty-per-cent. strength and one part ofconcentrated solution of formic aldehyde and shake the whole until aclear solution results, which occurs in a short time. After allowingthis solution to stand for about fifteen to twenty hours at roointemperature the liquor is acidulated with hydrochloric acid. Thecrystallization of the 3-methyl-oxymethylene uric acid begins in theform of colorless crystals. cooling the mass for several hours withicewater the liquor lSIlllOVGd from the crystals by decanting,siphoning, or like. The analysis of the crystalline powder so obtainedafter being dried in an eXsiccator or in any suitable manner givesfigures corresponding to the formula O l-l N O or acid may readily beobtained from crystal- 2 IIN-CO oo o-N.on on.

1 This new compound is readily soluble in boilin g water, crystallizingtherefrom in the form of colorless prisms for the most part aggregatedin druses or nodules. a longer period formaldehyde escapes and j3-niethyl-uric acid is regenerated.

On boiling for It pos- Tsesses no melting-point, but is decomposedbetween 310 and 320 centigrade, this action being accompanied bydarkening and eifer- After vescence or frothing. It gives the murexidtest and reduces ammoniacal silver solution even when gently heating.

3-methyl-oxymethylene-uric acid is readily soluble in dilute alkalies,including ammonia, and also in fuming hydrochloric acid. I take one partof this 3-methyl-oxymethylene-uric acid and dissolve the same in eightparts of fuming hydrochloric acid, and add to the solution from five tosix parts of tin. This mixture is allowed to stand while being cooledwith ice-water. After the reduction under these conditions has takenplace for about twenty hours the separation of the 3-7-dimethyl-uricacid formed begins, the same being thrown outin the form of coarsegranular crystals. As soon as the evolution of hydrogen gas becomes lessenergetic it is accelerated by the introduction of some gaseoushydrochloric acid. After the lapse of about forty hours the liquor ispoured oif from the undissolved tin and diluted with water, (abouttwenty parts, by weight.) The dim ethyl-uric acid is thus thrown out inthe form of crystals, from which the mother-liquor is drained, siphoned,or decanted or removed in any suitable manner. After redissolving thesame in dilute ammonia solution and treatment with carbon and finallyprecipitating with hydrochloric acid the pure 3-7-dimethyl-uric acid,corresponding in every respect to thebody described in Berichte clcrDeatschen Ohe'mt'schen Gescllschaft, Vol. 28, page 2482, is obtained.

III. Preparation of 1-3-7-irimethyZ-uric acid, (hg clroazy-cafilein-.)Inthis process I again employ as a starting material a body described andcovered in the aforesaid application Serial No. 678,331, viz:1-3-dimethyl- 7 -oxymethylene uric acid, whose mode of preparation andcharacteristics I will first describe for the purpose of a fulldisclosure of my inventions Preparation of 1-3-dimczfhyl-oxymethgZcneuric acid.-I pour over one part of 1-3-dimethyl-uric acid 3.5 parts,by volume, of double normal potash-lye. This causes solution of theacid. After a short time, however, the whole congeals to a pulp or massof fine acicular crystals, consisting of the potassium salt of the1-3-dimethyl-uric acid. One part of concentrated solution offormic-aldehyde is now added, which rapidly results in the formation ofa clear solution. This solution is allowed to stand, and after some timethe potassium salt of the 1-3-dimethyl-oxymethylene-uric acid isseparated as a colorless crystalline mass, consisting of small needlesaggregated into globular masses. After allowing this crystalline mass tostand for about thirty hours the liquor is drawn ofi therefrom and thecrystalline mass is dissolved in water and acidulated with hydrochloricacid. The crystallization of the free 1-3-dimethyl-oxymethylene-uricacid in the form of colorless fine needles then begins. After coolingthe mass for several hours with ice-water the liquor is drawn olf fromthe crystals by siphoning, decanting, or otherwise. An analysis of thesecrystals after being dried by means of the exsiccator gives figurescorresponding to the formula O H N O or, structurally:

orI,.N oo

This new acid is soluble in water with tolerable ease and crystallizestherefrom in the form of colorless short prisms. On boiling with waterformic-aldehyde is quickly split 0%, 1-3-dimethyl-uric acid beingregenerated. The new product is, moreover, soluble in dilute alkalies,including ammonia, and also in concentrated hydrochloric acid. It has nomelting-point, but on boiling to over 300 centigrade it isgraduallydecomposed, the decomposition being attended by darkening.

When employing the alkylized uric acids as starting materials, thecorresponding oxymethylene compounds may also be obtained if theformic-aldehyde be added to a neutral instead of an alkaline solution ofsuch alkyluric acid. For these uric acids the generic feature of theprocess is the addition of formic-aldehyde to a non-acid solution of theuric acid.

In preparing the 1-3-7-trimethyl-uric acid I take one part of the1-3-dimethyl-7-oxymethylene-uric acid and dissolve it in five parts, byvolume, of hydrochloric acid and add five to six part-s of tin to thesolution. This mixture is allowed to stand while being cooled withice-water. After the reduction under these conditions has taken placefor about twenty hours and after the same is continued at roomtemperature for about twenty hours the liquor is diluted with abouttwenty parts of water. Then after filtering from undissolved tin cooledwith ice-water for several hours, whereby regenerated 1-3- dimethyl-uricacid is thrown out. After removing these crystals the liquor isevaporated in the water-bath to dryness as nearly as possible. Theresidue is taken up with about ten parts of cold water and the colorlessliquor is allowed to stand for some time, where l-3-7-trimethyl-uricacid or hydroxy-caffein crystallizes out in the form of fine needles.The remainder of hydroXy-cafiein is obtained by extracting bya suitablesolvent-such, for

example, as chloroform. The compound so ob.-

as set forth.

5. The process of preparing 7methyl-uric acid which consists indissolving oxy-inethylene-uric acid in hydrochloric acid, heating thesolution and adding thereto tin, all in the proportions and theconditions, substantially as set forth, then evaporating the solutionand taking up the residue with alcohol.

In testimony whereof I aflix my signature in presence of two witnesses.

FRITZ ACH.

Witnesses:

LORENZ ACH, GUSTAV HEINRICH.

